Today in Linus Pauling: March 19

Wrote these Manuscripts:Vitamin C and the Common Cold: An Up-To-Date Discussion, March 19, 1975.

Chemotherapy, March 19, 1987.

Gave these Speeches:Melting Points, Boiling Points, Crystal Energy, Fifth Lecture, Seminar on the Properties of Monatomic Atoms and Ions, University of California, Berkeley, March 19, 1929.

Perturbation Theory — Method of Variation of Constants, Second Lecture, Berkeley Lectures, Second Series — Introduction to Quantum Mechanics of Aperiodic Processes, University of California, Berkeley, March 19, 1930.

Structure and Specificity, Eli Lilly and Company, No Location, March 19, 1946.

The Third Party Movement in the United States, The English Speaking Union, Oxford University, England, March 19, 1948.

Disarm or Die!, Toronto Committee for Disarmament, Toronto, Canada, March 19, 1961; Causes of Aging and Death, University of Toronto, March 20, 1961.

Science and the Future of Humanity, American Friends Service Committee, Western Michigan University, Kalamazoo, Michigan, March 19, 1963.

The Health and Welfare of Children: Future Directions, Sixth Annual Conference of the Quebec Association for Children with Learning Disabilities, Montreal, Canada, March 19, 1981.

In a 1997 interview with Jill Wolfson and Tejinder Singh, Alejandro Zaffaroni shared what it was like for him growing up in Montevideo, Uruguay, where he was born on February 27, 1923. He described himself as “kind of a sick child” with asthma severe enough to keep him isolated from his peers. As a boy he spent his time alone outdoors playing, exploring, and thinking about what he found. And when not playing outside, he attended a Jesuit school where he rebelled against the strict disciplinary regime. Zaffaroni described this as an opportunity to “think a lot about all kinds of strategies,” a skill that came in handy in his adult life.

As Zaffaroni transitioned into a public school at the age of twelve, his mother passed away. His father, a banker, began to spend more time with the boy, exposing him to the cultural life of Montevideo through the symphony, opera, and other outings. Encouraged by his father to develop his own interests, Zaffaroni found chemistry and, with the help of a friend who had a much better grasp of the content than the rest of the class, found a subject he could excel in. Unfortunately, just five years after his mother had done so, Zaffaroni’s father also passed away. Yet his example continued to inspire his son.

As a pre-med student at the University of Montevideo, Zaffaroni encountered biochemistry, a subject he pursued further as the first Uruguayan to enroll in a biochemistry Ph.D. program in the United States. In July 1945 he headed to Rochester University which Zaffaroni chose over other options, including Harvard, because of the promise of freedom to follow his own research path in endocrinology, with a focus on steroids. After finishing his doctorate in 1949, he continued his work with steroids with the support of a grant from the National Institutes of Health and published his first article, “Adrenal Cortical Hormones,” in Science with Robert B. Burton and E. Henry Keutmann.

Finished with his education and ready for the next step, Zaffaroni had his pick of offers from several universities and private labs. Harvard again appeared to be a possibility, one that briefly brought him to the attention of Linus Pauling. In 1953, George. B. Kistiakowsky of Harvard wrote to Pauling for advice on a list of candidates for a new biochemistry professorship that included “Alessandro Zaffaroni.” Pauling underlined two names, Frank H. Westheimer, which he annotated with “best,” and Zaffaroni, which he annotated with “never heard of him.” Zaffaroni chose another path as Westheimer ultimately got the position, delaying further contact between Zaffaroni and Pauling for another fifteen years.

Continuing to follow his father’s earlier directive that he seek out what interested him most, Zaffaroni also turned down a position at the newly established Sloan-Kettering Institute which, according to a 2012 article in Life Sciences Foundation Magazine, had “one of the world’s top steroid labs.” Expanding on an established relationship with George Rosenkranz at Syntex, Zaffaroni chose instead to head to Mexico City to work for the smaller company, where he felt he would have fewer restrictions on his own research. At this time, in 1953, Zaffaroni also received his first patent, which concerned the extraction of adrenal hormones from bovine and porcine adrenal glands.

At Syntex, Zaffaroni worked on synthesizing steroids using a phytoestrogen extracted from yams. When he noticed that the quality of the yams interfered with the process, he went to the supplying yam farm himself and reorganized harvesting and transportation while also increasing its worker’s wages. Zaffaroni’s efforts were noticed by Charles Allen, who bought Syntex in 1956 and gave the young researcher a promotion. Zaffaroni and Rosenkranz quickly built the company into a major supplier of topical corticosteroids.

In 1962 Zaffaroni was named president of Syntex’s subsidiary in Palo Alto, California, and given the specific charge to gain access to the US pharmaceutical market. The company entered the nascent birth control pill market in 1964 and started creating offshoot companies to take advantage of Syntex’s various lines of research. This led to the creation, in 1966, of the Syva Corporation, which produced diagnostic equipment, as well as the pest control company, Zoecon, incorporated in 1968.

In addition to his executive duties, Zaffaroni also began thinking about new methods of drug delivery, but the culture at Syntex was not supportive of this work. So, funded by $3 million of his own money, Zaffaroni started ALZA in 1968 to focus on this new path of research. ALZA’s main products included an ocular insert designed to administer glaucoma medication, an intrauterine device for birth control medication, and transdermal patches, each of which incorporated timed release mechanisms. Though ALZA’s products were innovative, the pharmaceutical market was hard to move as eye drops, pills, and injections maintained their dominance.

The creation of ALZA, Inc., based in Palo Alto, coincided with Linus Pauling’s move to Stanford University in 1969. In March of that year, Zaffaroni introduced himself to Pauling, writing that he was “extremely pleased” that Pauling would soon be nearby and noting his eagerness to talk with Pauling in person about the burgeoning field of orthomolecular psychiatry. By enclosing some company literature, Zaffaroni also got Pauling interested in ALZA. The two met in April as Linus and Ava Helen were in the midst of their house hunting. The meeting was especially fruitful for Pauling as Zaffaroni provided him with a $100,000 grant to be divided over his next four years at Stanford.

For the next few years the two maintained an informal relationship by visiting each other, sharing ideas, and extending invitations to social gatherings. In 1974 Pauling brought a formal element to their relationship by asking Zaffaroni to become a member of the Board of Associates of the Linus Pauling Institute of Science and Medicine, at that point still in its infancy. Zaffaroni told Pauling in November, “I have been approached by many groups to participate in directorships of various worthwhile organizations, and have been forced to decline. But because of my great admiration for you and for your accomplishments, I am prepared to accept.” He warned Pauling that his busy schedule might interfere at times and in reply Pauling promised that he would not make too many demands. Zaffaroni’s fundraising experience quickly became central to his activities as an associate and he began a correspondence with Art Robinson – at that time LPISM’s Assistant Director – concerning the development of a prospectus for potential donors.

In the summer of 1975, Pauling asked Zaffaroni to extend his relationship with the Institute by joining its Board of Trustees. Again, Pauling promised that Zaffaroni’s duties would be minimal. Zaffaroni made one stipulation in his acceptance: that the Institute revisit the operation of its fledgling medical clinic. Zaffaroni told Robinson that the psychiatric research going on at the clinic needed a better review system. Robinson responded by suspending all outpatient services at the clinic. By November, with the changes in place, Zaffaroni agreed to join the Board.

In his new capacity, Zaffaroni continued his involvement in helping Robinson with fundraising. Their first outreach effort involved “two popular appeals,” one in Prevention and the other in Executive Health. The Institute published an article in both publications and placed a request for donations at the end of each one. Robinson reported to Zaffaroni in March 1976 that the Prevention article had generated 183 donations worth $5,101.50 while the Executive Health article received 103 donations worth $8,031.50.

(Life Sciences Foundation image)

Besides running ALZA and serving on the Board at LPISM, Zaffaroni continued his own scientific work. This included “Special requirements for hormone releasing intrauterine devices,” published in Acta Endocrinologica in 1974, and “Contraception by intrauterine release of steroids,” which appeared in the Journal of Steroid Biochemistry in 1975. He also received patents for his transdermal bandages in 1974 and 1976, and patents for controlled release tablets in 1976 and 1977. The following year he published an article, “Therapeutic Systems: The Key to Rational Drug Therapy,” in Drug Metabolism Reviews, that described some of his new developments.

Pauling tried to tie in his own interests to these drug delivery systems. In March 1979, Pauling wrote to Zaffaroni about a study on the improvement of patients with anorectal cancer who were given time released capsules of ascorbic acid. Pauling saw the improvement as being due to topical effects and shared his idea for a similar “slow release” capsule for stomach cancer, which was then afflicting Ava Helen. Pauling’s capsule would “spring into the shape of a sphere, which would cause it to be retained in the stomach” as the ascorbic acid was released into the stomach and afterwards broken down and digested. Zaffaroni responded that ALZA was already at work on something similar to what Pauling described and that he was eager to talk more about it. By 1986 ALZA had released a “once-a-day” Vitamin C supplement utilizing its controlled-release technology.

Amidst the biotech boom of the early 1980s, Zaffaroni’s business practices came under closer examination. In 1982 Time highlighted Zaffaroni’s recent start-up, DNAX, as one of the genetic engineering companies “having trouble living up to their early billing” as one of the “hottest companies on Wall Street.” The article pointed out that to start the company Zaffaroni had “easily raised $5.5 million,” but was now “spending nearly $4 million annually on research, and…does not expect to see any profits for at least another six or seven years.” Other sources in the popular press were often more critical, focusing on Zaffaroni’s commercial, rather than scientific, performance.

In August 1985, Zaffaroni decided to resign from LPISM’s board. He felt that his work was done, telling Pauling that the Institute “has now attained worldwide recognition” and that, with Pauling’s “guidance it will continue to evolve in many positive directions.” He continued

My pattern, as you know, has been to participate in the founding of various enterprises and, once they are established, to go on to new ones. That is because I believe that what is done initially counts more than anything else. Thus, my focus has generally been on contributing innovative concepts at the outset rather than remaining permanently associated with any particular endeavor. That pattern enables me to do what I do best and to keep from becoming stale. It also leaves room for others to follow with fresh insights and new concepts. Thus, I believe it serves everyone well.

I am sure that you know, without my saying it, that the main inducement to my acting as Trustee has been the opportunity it gave me to work with you. That association has brought me great personal pleasure, intellectual challenges, and a keen appreciation of your many gifts of heart and head. You may be sure that I stand ready to help you at any time in any way I can, should the need arise.

Zaffaroni did, however, remain on the Institute’s Board of Associates until 1996 and maintained his connections to LPI into the 2000s when he met with longtime administrative officer Stephen Lawson in Palo Alto to discuss the Institute’s collaborative research on ALS and peroxynitrite in Uruguay.

Congratulatory note from Pauling to Zaffaroni on the occasion of Zaffaroni being honored by the Weizmann Institute of Science, November 1989.

After leaving LPISM, Zaffaroni also stepped down as ALZA’s CEO to seek out new endeavors. In 1988 he asked Pauling to become the Honorary Scientific Advisor for the newly forming Affymax Research Institute. As part of the deal, LPISM received 25,000 shares of stock in the company. By June 1990, Zaffaroni told Pauling that Affymax was “moving from an early stage ‘start-up’ to a successful development stage pharmaceutical company.”

The press continued to be somewhat cautious. The following year, the New York Times still referred to Affymax as a promising start-up, but was concerned with Zaffaroni’s avoidance of investment bankers by relying on his many contacts to raise his own funds. The Times followed up with questions as to how Affymax “burned through over $20 million so fast” and by noting that its central product -VLSIPS, short for Very Large Scale Immobilized Polymer Synthesis, which were biological compounds produced on silica chips developed by the semiconductor industry – was not selling well. Zaffaroni was not concerned with Affymax’s profitability at all, informing Pauling in May 1991 that he had raised $26 million and was ready for the company to “aggressively pursue our scientific and commercial goals” as well as move into their new research facility. By the end of the year, Affymax began offering public stock.

At the end of the 1990s, Zaffaroni began attracting more praise in the press, particularly for his founding, in 1995, of Smyx, a company focusing on the applications of combinatorial chemistry in the development of drugs. But he was also running up against new criticism echoing that issued in the early 1980s about the viability of DNAX. This time those fears were directed at Affymetrix, which had been spun off from Affymax in 1992 to focus on VLSIPS. An article in Forbes reported that the chips, though potentially “a godsend to medicine,” may not be a “godsend…to Affymetrix’s bottom line.”

Zaffaroni soon had more direct problems to deal with. In 1995 he organized the sale of Affymax to Glaxo for $533 million. Some of Zaffaroni’s friends and family members began trading shares of Affymax just before the sale was announced publicly, which drew the attention of the Securities and Exchange Commission. Charged by the SEC with insider trading, Zaffaroni and six others agreed to pay fines of $1.85 million and immediately tried to move on. According to the New York Times, Zaffaroni’s lawyer stated that his client wanted “to devote his time to science and charity rather than litigation.” And that’s just what he did as he continued to produce more patents related to drug delivery and VLSIPS.

The 2000s saw Zaffaroni open up another line of research, this time for a drug delivery system that used the cigarette as a model. In 2000 Zaffaroni started Alexza to focus on this research and, before too long, he, along with Joshua D. Rabinowitz and Dennis W. Solas, produced patents for delivering insomnia, anti-inflammatory, antipsychotic, pain relieving, and several other drugs through inhalation. Unlike other inhalation drugs, these relied on the slight heating of the drugs before delivery. Zaffaroni and others described their research in “Fast Onset Medications through Thermally Generated Aerosols” for the Journal of Pharmacology and Experimental Therapeutics in 2004. In 2012 Alexza’s first product, aimed at schizophrenia and bipolar disorder, was ready for market. That same year, at the age of 89, Zaffaroni was inducted into the National Inventors Hall of Fame.

Zaffaroni passed away this past March 1st from complications related to dementia. When asked in 1997 how he wanted to be remembered, Zaffaroni said

Well, the one thing that was always very important in my life is human relations. So in looking at candidates for any of the jobs that I had, I wanted to have people who shared my value system, in addition to being the kinds of capable individuals that I needed to have.

Perhaps drawing on his father’s support and encouragement of him as a youth, Zaffaroni continued,

It is tremendously important in building this company that I create a very, very warm caring environment, so that people have an opportunity to do the best of their work. One of the key things to success is never to worry about failing. Many people do not do a lot of the things that could be done because they do not want to have a negative result. If you don’t go for the new breakthrough, if you are going just to stay in the areas which we all know, we are stationary.

Now on the other hand, if you make a huge effort with a new idea and you don’t succeed, the big companies don’t see that as a good thing. So why take risk, if there is no opportunity to be rewarded by the effort?

In my view, the only thing attractive in life is continually to move forward, to be looking for new opportunities, and to support people and let them fail safely.